Spinal arthrodesis procedures are commonly performed in our veterans for a wide range of pathology. Despite state-of-the-art surgical procedures, fusion failure rates still range from 10-40%. This is important, as failure to fuse is often associated with continued pain, worse outcomes, increased medication requirements, and possibly the cost of additional surgeries. Given the individual shortcomings of the currently available bone graft options, there is a clear clinical need for additional strategies that the surgeon can utilize in order to achieve consistently successful spinal fusions. We have specifically identified an opportunity to address this clinical problem by taking advantage of the complex crosstalk between the Wnt and BMP signaling pathways. Promotion of canonical Wnt signaling through blocking the Wnt inhibitor sclerostin represents a unique opportunity to enhance bone formation locally. The cumulative literature on sclerostin inhibition suggests that an anabolic bone forming effect can be achieved while simultaneously decreasing bone resorption. As such, sclerostin inhibition is the only known anabolic strategy that leads to an uncoupling of bone formation and resorption in humans. The majority of sclerostin blocking strategies involve monoclonal antibodies (mAbs) delivered systemically, which is not ideal in local bone healing applications like posterolateral spine fusions. Systemic dosing, as compared to local delivery, typically requires higher dosing regimens and raises concern over the potential for off-target side effects. mAbs also have limited stability and a short shelf-life, are prone to batch-to-batch variation, and are difficult to engineer into a carrier. In addition, their high manufacturing cost will continue to be a limitation as we move towards a more value-based healthcare economy. Using the pioneering work of anti-sclerostin mAbs as a demonstration of the viability of sclerostin blockade, we propose to investigate a novel and highly innovative strategy based on the local delivery of small molecule inhibitors (SMIs) of sclerostin. We believe that SMIs are more advantageous than mAb-based strategies for local bone formation because of multiple key factors: ease and consistency of manufacturing, improved stability, immunoprivilege, controllable spatial and temporal release, and significantly reduced cost. The goal of this application is to demonstrate that a single administration of a locally delivered anti-sclerostin SMI at the time of spinal arthrodesis surgery will result in a lower pseudarthrosis rate compared to autologous ICBG (the gold standard). Certainly, a reduced spinal pseudarthrosis rate in our veterans will directly lead to better outcomes as well as a decrease in the overall cost associated with these commonly performed surgeries. We have utilized a validated in silico strategy to computationally identify two FDA approved compounds with the potential to be repurposed as anti-sclerostin SMIs. Here, we provide compelling preliminary evidence that these SMI candidates can enhance Wnt/?-catenin and BMP signaling as well as promote mineralization in vitro, indicating that these SMIs may represent a novel cost-effective biologic bone graft enhancer. Therefore, our central hypothesis posits that a locally delivered SMI of sclerostin will promote local bone formation within a spine fusion bed via enhancement of Wnt/?-catenin in both migrating mesenchymal stem cells (MSCs) and resident osteoblasts at the fusion site while transiently inhibiting osteoclastic bone resorption. To verify our hypothesis, we first propose to demonstrate that the SMI candidates have their expected target and mechanism of action. Next, we will test each SMI for their ability to induce ectopic de novo subcutaneous mineralization in a challenging rat model. Finally, we intend to demonstrate that locally delivered anti-sclerostin SMIs enhance successful spine fusions in rabbits. This CDA, under the mentorship of an interdisciplinary research team, will help round out the PI?s research knowledgebase and will arm the PI with the necessary skillset to develop a highly translational VA research program that focuses on bringing research from the lab to the clinic in a timely manner in order to have the greatest possible impact on veterans.